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Diagnosis and treatment of cancer
Colour-enhanced X ray showing a tumour (yellow) of the right lung.
Athenais/Phototake
Greater insight into the causes and mechanisms of cancer has led to better ways to diagnose and treat the many forms of this disease. First of all, advances in detection have improved the ability to discover cancers earlier and to diagnose them more accurately than was the case only a few years ago. (Indeed, some tests can identify precancerous tumours before symptoms appear and thus can be used to prevent cancers from developing.) In addition, improvements in conventional cancer treatments can cure many cases of cancer, and new therapeutic strategies show promise of being even more effective in thwarting the disease. This section reviews both conventional and innovative methods of diagnosing and treating cancer.
Diagnostic procedures
In order for cancer to be diagnosed as early as possible, an individual should be aware of symptoms that may be related to the disease. The American Cancer Society lists seven basic warning signs of cancer: unusual bleeding or discharge, persistent hoarseness or cough, changes in bowel or bladder habits, a persistent thickening or lump, a sore that does not heal within two weeks, indigestion or trouble swallowing, and a change in the appearance of a mole or wart.
The physician evaluating a person with any of these symptoms comes up with a diagnostic workup to determine whether a tumour is present and, if so, whether the growth is benign or malignant. The diagnostic methods employed depend on the type and location of the suspected tumour.
A patient undergoing a computed tomography (CT) scan of the abdomen. On the monitor at the right …
Simon Fraser/Main X-Ray, Newcastle General Hospital/Science Photo Library/Photo Researchers
Computed tomography (CT) scan of a cross section of the human abdomen, showing cancer of the liver. …
Dept. of Clinical Radiology, Salisbury District Hospital/Science Photo Library/Photo Researchers
The standard diagnostic workup begins with a detailed clinical history of the person. A complete physical examination, including laboratory tests such as a complete blood count and a urinalysis, is made. Diagnostic imaging using X rays, ultrasound, computed tomography (CT) scans, or magnetic resonance imaging (MRI) may be essential, and radioisotopes can be used to visualize certain organs or regions of the body. If necessary, the physician can use an endoscope to inspect the internal cavities and hollow viscera. An endoscope is an optical instrument that makes it possible not only to observe the appearance of the internal linings but also to perform a biopsy, a procedure used to procure a tissue sample from a lesion for evaluation.
Biopsy
Stereotatic biopsy of a suspected breast tumour. Using data supplied by previous imaging, the …
Mednet/Phototake
Biopsies, the most definitive diagnostic tests for cancer, can be performed in the physician's office or in the operating room. There are different techniques. In excisional biopsy, the entire tumour is removed. This procedure is carried out when the mass is small enough to be removed completely without adverse consequences. Incisional biopsies, which remove only a piece of a tumour, are done if the mass is large. Biopsies obtained with visual control of an endoscope consist of small fragments of tissue, usually no larger than 5 millimetres (0.2 inch) long. Needle biopsy involves the removal of a core of tissue from a tumour mass with a specially designed needle often under imaging guidance. Alternatively, the needle can be stereotactically guided to a previously localized lesion. This type of biopsy yields a tissue core or cylinder and is frequently used for the diagnosis of breast masses and biopsies of brain lesions.
Another type of biopsy, called fine-needle aspiration biopsy, yields cells rather than a tissue sample, so that the pathologist is able to assess only cellular features and not the architectural characteristics of the tumour tissue. Nevertheless, fine-needle aspiration has many positive qualities. It is relatively painless and free of complications. In many instances it is a worthwhile adjunct to the diagnosis. Unlike a tissue sample, which may take two days to examine, a sample obtained by fine-needle aspiration can be examined and interpreted within a day or even in a matter of hours.
When it is necessary to identify the nature of a mass during a surgical operation, a biopsy can be performed and the tissue sample frozen for microscopic examination. Following this quick method, samples of tissue are frozen and then sliced into thin sections that are stained and examined under the microscope. Frozen sections are also used to assess whether the tumour has been completely excised. This is done by taking tissue samples from areas adjacent to the tumour to confirm that all diseased cells have been removed. In general, the rate of diagnostic accuracy of frozen sections is 95 to 97 percent.
Biopsy interpretation is a highly accurate technique that is supplemented with special methods of examination. Tissue sections can be viewed with an electron microscope, or they can be stained, using an immunohistochemical approach that uses antibodies directed against tumour-associated antigens. Molecular biological techniques can be employed to detect mutations in proto-oncogenes and tumour suppressor genes, and cytogenetic tests can be performed on tissue samples to analyze the chromosome content of the cells.
Evaluation of tumours
Grading and staging
A major factor governing the choice of therapy is the grade and stage of the tumour. In many cases grading and staging schemes can help to predict the behaviour of a tumour and thereby determine the most appropriate approach to treatment.
Grading schemes classify tumours according to the structure, composition, and function of tumour tissue—in clinical terms, the histological features of the tumour. The histological grade of a tumour refers to the degree of tissue differentiation or to an ensemble of tissue features that have been found to be a good predictor of the aggressiveness of the tumour. Most grading schemes classify a type of cancer into three or four levels of increasing malignancy.
Staging protocols, which are independent of grading schemes, are employed to describe the size and dissemination of the tumour, both in the organ in which it arose and beyond it. For every type of tumour, a series of tests and procedures are codified in order to assess how far the tumour has extended in the patient's body. Each tumour staging system is complemented by a grading method.
An internationally standardized classification system is the TNM staging system, put forth by the Union Internationale Contre le Cancer and the American Joint Committee on Cancer. In this system T refers to the size of the primary tumour, N to the presence and extent of lymph node metastases, and M to the presence of distant metastases.
Molecular evaluation
Besides stage and grade, other prognostic factors exist for many types of cancer. Cancers can be defined not only by their appearance but also by the pattern of altered gene activity. Definition of this altered pattern by molecular tests can help to predict the rapidity of growth of the tumour, its tendency to spread, and its response to therapies.
Molecular procedures, when integrated with conventional grading and staging procedures, are likely to improve significantly the present systems of prognostication. Some are based on detecting and measuring the level of substances produced by the tumour. These substances, called tumour markers, also can aid in monitoring an individual who has received treatment for cancer to determine whether the tumour has returned. A rising level of a tumour marker in the blood will in general indicate the regrowth of the tumour. Diagnostically useful tumour markers include carcinoembryonic antigen (CEA), which is an indicator of carcinomas of the gastrointestinal tract, lung, and breast; CA 125, which is produced by ovarian cancers; CA 19-9, which indicates pancreatic or gastrointestinal cancers; and alpha-fetoprotein and chorionic gonadotropin, which can indicate testicular cancer.
Tumour markers also can be used to estimate the proportion of cells in a tumour that are actively growing. This approach has prognostic significance because tumours with a high proportion of dividing cells tend to be more aggressive.
It is often the case that the more abnormal the DNA content per cell, the more difficult the tumour will be to control. It is possible to refine the prognosis of a tumour by examining the specific genetic alterations found in the cells of the tumour. For example, neuroblastoma cells that contain amplified amounts of the N-MYC gene indicate a worse prognosis for the individual than do cells from identical tumours that have the normal genetic complement of N-MYC (see the section Causes of cancer: Gene amplification).
A sensitive molecular technique called the polymerase chain reaction (PCR) makes it possible to detect mutations that identify certain tumours when only a small number of cancer cells are present. For example, in individuals with leukemia who have received bone marrow transplants, a PCR assay can discover very low levels of residual malignant cells in the circulation and thus provide a sensitive indicator of the success of the therapy.
Therapeutic strategies
Once a diagnosis of cancer has been established, a plan for treatment is needed. A therapeutic strategy is best achieved by a multidisciplinary team of physicians that includes surgeons, medical and radiation oncologists, diagnostic radiologists, pathologists, and—depending on the operations planned—plastic and reconstructive surgeons or physical rehabilitation specialists.
Therapeutic strategies must be tested in experimental trials using specific scientific methods and standards before they are proven effective. The largest risk in using unproven approaches is that they may cause a delay in treatment with a proven method.
Conventional therapies
Surgery, radiation, and chemotherapy alone or in combination are the most common methods used to treat cancer. The specific treatment will vary depending on the kind of cancer, the extent of the disease, its rate of progression, the condition of the patient, and the response to therapy.
Surgery
Surgery is the oldest form of cancer therapy and was until recently the only method that could actually cure cancer. It is still the principal cure.
Although new advances in surgical techniques have allowed for the successful removal of many cancers, the development of other treatment strategies has reduced the extent of surgical intervention in treating some cancers. And in spite of new surgical techniques, the ability of surgery to control cancer is limited by the fact that, at the time of surgical intervention, two-thirds of cancer patients have tumours that have spread beyond the primary site.
In planning the definitive treatment of an individual with a solid tumour, the surgical oncologist confronts several challenges. One major concern to be addressed is whether the patient can be cured by local treatment alone and, if so, which type of operation will provide the best balance between cure and impact on the quality of life. With many tumours the magnitude of the resection is modified by adjuvant therapies. Therapy also has improved by combining surgery with other types of treatment. For example, survival rates of childhood rhabdomyosarcoma (a type of muscle tumour) were only 20 percent when radical surgery alone was used. However, when adjuvant radiation therapy and later chemotherapy were used in combination with surgery, cure rates rose to 80 percent.
Although surgery often is intended to be curative, it may sometimes be used to assuage pain or dysfunction. This type of surgery, called palliative surgery, can remove an intestinal obstruction or remove masses that are causing pain or disfigurement.
Certain conditions associated with a high incidence of cancer can be prevented by prophylactic surgery. One such condition is cryptorchidism, a developmental defect in which the testes do not descend into the scrotum (which creates a risk of developing testicular cancer). A surgical procedure called orchiopexy can correct this defect and thereby prevent malignant disease from occurring. Diseases including multiple polyposis of the colon and longstanding severe ulcerative colitis are associated with a high risk for colon cancer, and they can be treated by partial or complete removal of the colon. Individuals with multiple endocrine neoplasia, who are at risk of developing medullary cancer of the thyroid, likewise can be treated by having the thyroid removed.
Radiation therapy
Radiation therapy is the use of ionizing radiation—X rays, gamma rays, or subatomic particles such as neutrons—to destroy cancer cells. Approximately 50 percent of all individuals diagnosed with cancer receive radiation therapy. Only surgery is more commonly used.
Cells are destroyed by radiation either because they sustain so much genetic damage that they cannot replicate or because the radiation induces apoptosis (or programmed cell death). Cancer cells are more sensitive to radiation than are healthy cells because they are continuously proliferating. This factor renders them less able to recover from radiation damage than normal cells, which are not always reproducing.
Clinical linear accelerator employed in a hospital setting to deliver measured doses of radiation …
Doug Martin/Photo Researchers
Different ranges, or voltages, of radiation are used in clinical practice. The lowest range is called superficial radiation; the medium range is called orthovoltage; and the high range is called supervoltage. Two techniques are used to deliver radiation therapy in the clinic: brachytherapy and teletherapy. In brachytherapy, also called internal radiation therapy, the source of radiation is placed directly into the tumour or within a nearby body cavity. Some of the substances used are radioactive isotopes of iridium, cesium, gold, and iodine. The devices used to contain the radioactive substances are diverse in form (e.g., tubes, needles, grains, and wires). Sometimes the radioactive source is delivered to the tumour through tubes and then withdrawn—an approach called remote brachytherapy. Teletherapy, or external radiation therapy, uses a device such as a clinical linear accelerator to deliver orthovoltage or supervoltage radiation at a distance from the patient. The energy beam can be modified to adapt the dose distribution to the volume of tissue being irradiated.
Once the decision has been made to use external beam radiation, a series of pretreatment procedures are performed. First, the precise location of the tumour is identified by means of magnetic resonance imaging (MRI). Next, the appropriate energy level is selected, and the beam distribution and dose distribution are carefully determined so as to maximize the therapeutic effect and minimize damage to healthy tissues. Precise irradiation requires devices (casts) that carefully position the patient. Sometimes markings are used to position and delimit the fields. This is necessary because radiation is administered in repeated small doses, called fractions. Fractionation minimizes complications and, when given at equal doses, allows for a more effective cure. For some tumours—including cancer of the uterine cervix, larynx, breast, and prostate, as well as Hodgkin disease and seminoma (a type of testicular cancer)—curative doses of radiation can be applied without causing serious damage to surrounding tissues.
The undesirable effects of radiation therapy are divided into acute and late effects. Acute effects occur in rapidly renewing tissues, such as the linings of the oral cavity, pharynx, intestine, urinary bladder, and vagina. Late effects, which are related to the total dose of radiation received, include scar formation (fibrosis), tissue loss, and creation of abnormal openings (fistulae). Secondary effects can be minimized by internal radiation, a form of therapy that delivers a high dose of radiation to the tumour with less exposure to normal tissues.
Radiation therapy is often combined with surgery. Although surgery is most useful in removing a localized tumour, it may fail to remove cells that have spread beyond the margins of the surgical procedure. Conversely, radiation therapy is most effective at eradicating undetected disease at the periphery of the tumour and least effective in killing cells at the centre of large tumours. Thus, in certain situations—such as the limited excision of a breast tumour (lumpectomy) followed by radiation therapy—the weaknesses of each therapy are offset by the strengths of the other.
Chemotherapy
Chemotherapy is the administration of chemical compounds, or drugs, to eliminate cancer cells. Chemicals destroy cancer cells by preventing them from multiplying. Unlike surgery or radiation therapy, which cannot treat widespread metastases, anticancer drugs can disperse throughout the body via the bloodstream and attack tumour cells wherever they are growing—with the exception of a few sites in the body known as “sanctuaries,” areas where the drug does not actually reach the tumour cells.
The first chemotherapeutic agent used against cancer was a nitrogen-mustard compound employed in the 1940s to treat Hodgkin disease and other lymphomas. There are now about 100 different drugs used in the treatment of cancer. They are classified by their structure and function as alkylating agents, antimetabolites, natural products, hormones, and miscellaneous agents. Chemotherapeutic agents are used in four situations: (1) They are chosen in some cases as the primary treatment for individuals with a localized cancer. (2) They are administered as the primary therapy for individuals with advanced cancer for which there is no other alternative therapy. (3) They are used as an adjunct therapy to radiation or surgery. (4) They are administered directly to sanctuaries that are not reached by the bloodstream or to specific regions of the body most affected by the disease.
With some notable exceptions—such as Burkitt lymphoma and choriocarcinoma—cancer cannot be eradicated with only a single chemotherapeutic agent. In order to produce a lasting clinical response, a combination of drugs is required. Combination chemotherapy was first used to treat leukemia and lymphoma. After considerable success in treating these malignancies, combination chemotherapy was extended to solid tumours.
Unfortunately, cancer cells can develop resistance to chemotherapy, just as bacteria can become resistant to antibiotics. One explanation for the development of drug resistance (and resistance to radiation as well) is that apoptosis (or programmed cell death) cannot be induced in certain cancer cells. It is known that both chemotherapy and radiation therapy kill cells by inducing apoptosis, essentially making the cell trigger the program of cell death rather than succumb to the action of the chemical itself.
The side effects of chemotherapy vary greatly among individuals and among drug combinations. Side effects arise because many chemotherapeutic agents kill healthy cells as well as cancer cells. Nausea, vomiting, diarrhea, hair loss, anemia, loss of ability to fight infection, and a greater propensity to bleed may be caused by chemotherapy. Many side effects can be minimized or palliated and are of limited duration. No relationship exists between the efficacy of a drug on a tumour and the presence or absence of side effects.
Bone marrow transplantation
One of the most life-threatening effects of high doses of chemotherapy—and of radiation as well—is damage that can be done to bone marrow. Found within the cavities of bones, marrow is rich in blood-forming (hematopoietic) stem cells, which develop into oxygen-bearing red blood cells, infection-fighting white blood cells, and clot-forming platelets. Chemotherapy can decrease the number of white blood cells and reduce the platelet count, which in turn increases susceptibility to infection and can cause bleeding. Loss of red blood cells also can occur, resulting in anemia.
One way to offset these effects is through bone marrow transplantation. Strictly speaking, bone marrow transplantation is not a therapy for most forms of cancer (two exceptions being leukemia and lymphoma). Rather, it is a means of strengthening an individual whose blood-making system has been weakened by aggressive cancer treatments.
Bone marrow transplantation
Encyclopædia Britannica, Inc.
There are two common approaches to marrow transplantation: autologous and allogeneic transplants. (The phrase stem cell therapy is more accurate than bone marrow transplantation, since it has become common whenever possible to collect stem cells from the blood.) An autologous transplant involves the harvesting and storage of the patient's own stem cells before therapy. After the patient has received high levels of chemotherapy or radiation to destroy the cancer cells, the stem cells are injected into the bloodstream to speed recovery of the bone marrow. If an individual's marrow is diseased—from leukemia, for example—a person with a matching tissue type is found to donate stem cells. This type of transplant, called an allogeneic transplant, carries the risk of mismatch between tissues—a situation that can stimulate immune cells of the host to react with the donated cells and cause a life-threatening condition called graft-versus-host disease. Because of the danger of this complication, autologous transplants are more commonly performed. In these cases the patient's stem cells can be removed, purged of cancer cells, and then returned.
Biological therapies
Biological therapy has emerged as an important “fourth” accepted method as a result of gains made in understanding the immune defenses against cancer. Progress in biotechnology has provided necessary quantities of biochemical molecules to support this therapy.
Angiogenesis inhibitors
Since the progression of tumours requires the development of capillaries (a process known as angiogenesis) that supply tumour cells with oxygen and nutrients, interfering with this essential step is a promising therapeutic approach. Antiangiogenic drugs have been shown in animal studies to shrink tumours by destroying the capillaries that surround them and by preventing the production of new vessels. In combination with conventional therapy, they might be useful in the treatment of cancer. They remain an object of intensive research.
Immunotherapy
Tumour-associated antigens are present on tumour cells, but they also are found on the surface of normal cells; in addition, these antigens are not specific to a certain type of tumour but are seen in a variety of cancers. Despite the lack of tumour specificity, some tumour-associated antigens can serve as targets for attack by components of the immune system. For instance, antibodies can be produced that recognize a specific tumour antigen, and these antibodies can be linked to a variety of compounds—such as chemotherapeutic drugs and radioactive isotopes—that damage cancer cells. In this way the antibody serves as a sort of “magic bullet” that delivers the therapeutic agent directly to the tumour cell. In other cases a chemotherapeutic agent attached to an antibody destroys cancer cells by interacting with receptors on their surfaces that trigger apoptosis.
Another immunologic approach to treating cancer is the so-called tumour vaccine. The object of a cancer vaccine is to stimulate components of the immune system, such as T cells, to recognize, attack, and destroy cancer cells. Tumour vaccines have been created by using a number of different substances, including tumour antigens and inactivated cancer cells.
Tumour-associated antigens also can be used as tumour markers. Because elevated levels of tumour-associated antigens indicate that the presence of a tumour is likely, they remain a useful tool either in screening for the recurrence of previously treated cancers or in preventive screening. For example, prostate-specific antigen (PSA) is used to screen for carcinoma of the prostate.
Other biological response modifiers that have been developed include interferon, tumour necrosis factor, and various interleukins. Interleukin-2, for example, stimulates the growth of a wide range of antigen-fighting cells, including several kinds that can kill cancer cells.
Gene therapy
Knowledge about the genetic defects that lead to cancer suggests that cancer can be treated by fixing these altered genes. One strategy is to replace a defective gene with its normal counterpart, using methods of recombinant DNA technology. Researchers are exploring methods that can insert genes into tumour cells.
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